CHICAGO, IL USA (UroToday.com) - Data suggests that there is an overall survival benefit associated with neoadjuvant chemotherapy among patients with muscle-invasive bladder cancer. Despite this, adoption of neoadjuvant chemotherapy remains slow in clinical practice. Additionally, many patients treated with neoadjuvant therapy receive a combination of gemcitabine and cisplatin (GC) chemotherapy, though data demonstrating efficacy does not exist for this regimen in the neoadjuvant setting.

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In light of this, Dr. Plimack and colleagues sought to evaluate the activity of neoadjuvant GC prospectively in a dose-dense manner that would allow rapid treatment and minimize delay to cystectomy. Included patients had muscle-invasive bladder cancer, cT2-T4a, were node negative, and had creatinine clearance > 50. Dose-dense GC was administered as follows: gemcitabine 1200 mg/m2, cisplatin 70 mg/m2 on day one with pegfilgrastim 6 mg on day 2 or 3. Patients with creatinine clearance between 50 and 60 ml/min received split dose cisplatin dosing on days one and 2. This cycle was repeated every 2 weeks, and patients were given a total of 3 cycles. Treatment extended over a 6-week period, which is significantly shorter than many GC regimens that include four 21-day cycles and take 12 weeks. Patients underwent radical cystectomy with lymph node dissection 4-8 weeks after completing chemotherapy. The investigators assessed pathology complete response (pCR) as the primary endpoint.

In total 32 patients were enrolled on the study over a 14 month period. Among 31 evaluable patients, 26 had T2 or T3 disease, and 25 received all 3 cycles of dose-dense GC. One patient required dose reduction of gemcitabine for thrombocytopenia. Six patients discontinued chemotherapy early due to grade 3/4 vascular events (3), grade 2/3 renal events (2), or grade 3 hematologic toxicity (1). Among the first 13 patients, two patients developed myocardial infarction (one of whom developed CHF rendering the patient ineligible for radical cystectomy), two patients developed venous thromoboembolism (one pulmonary embolus (PE), one deep venous thrombosis (DVT)), and one required a CABG between chemotherapy and radical cystectomy. Despite protocol amendments that specified cardiac clearance requirements prior to enrolling in the study, one additional patient developed DVT and one patient experienced stroke. This induced the study closure prior to reaching the pre-specified accrual goal of 44 patients.

Of the 31 evaluable patients on study, 30 underwent radical cystectomy, with median time from start of chemotherapy to surgery of 9.3 weeks, 32% had a pCR, and 13% were downstaged to non-muscle invasive disease. Within the median follow-up period of 36 weeks, 5 patients have died, 2 due to metastatic disease. Ultimately the investigators conclude that although pCR rates are similar to those achieved with accelerated MVAC in prior studies, dose-dense GC is associated with significantly greater toxicity, particularly vascular toxicity including DVT, stroke, MI, and PE.

This study illustrates the heightened risk of thromboembolic events among bladder cancer patients, particularly those treated with gemcitabine containing regimens, although this rate of complications was not apparent in studies of advanced urothelial cancer patients. Careful attention by clinicians to vascular events is warranted. Dose-dense GC does not appear to improve pCR rates as compared to accelerated MVAC, and may result in worse morbidity and mortality in this population. Dose-dense GC is not currently being pursued for further therapeutic use in this patient population.